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The genetic background of ACTH-producing NENs has not been well studied. Inspired by an index case of ACTH-producing pancreatic NEN carrying a gene fusion, we postulated that ACTH-producing NENs might be enriched for gene fusions. We herein examined 21 ACTH-secreting NENs of the pancreas (10), lung (9), thymus (1), and kidney (1) using targeted RNA sequencing. The tumors were classified according to the most recent WHO classification as NET-G1\/typical carcinoid (<jats:italic>n<\/jats:italic>\u2009=\u20094), NETG-2\/atypical carcinoid (<jats:italic>n<\/jats:italic>\u2009=\u200914), and NET-G3 (<jats:italic>n<\/jats:italic>\u2009=\u20093). Overall, targeted RNA sequencing was successful in 11 cases (4 of 10 pancreatic tumors, 5 of 9 pulmonary tumors, and in the one renal and one thymic tumor). All four successfully tested pancreatic tumors revealed a gene fusion: two had a <jats:italic>EWSR1::BEND2<\/jats:italic> and one case each had a <jats:italic>KMT2A::BCOR<\/jats:italic> and a <jats:italic>TFG::ADGRG7<\/jats:italic> fusion, respectively. <jats:italic>EWSR1<\/jats:italic> rearrangements were confirmed in both tumors with a <jats:italic>EWSR1::BEND2<\/jats:italic> by FISH. Gene fusions were mutually exclusive with <jats:italic>ATRX<\/jats:italic>, <jats:italic>DAXX<\/jats:italic>, and <jats:italic>MEN1<\/jats:italic> mutations (the most frequently mutated genes in NETs) in all four cases. Using RNA-based variant assessment (<jats:italic>n<\/jats:italic>\u2009=\u200916) or via the TSO500 panel (<jats:italic>n<\/jats:italic>\u2009=\u20095), no pathogenic BCOR mutations were detected in any of the cases. Taken together, gene fusions were detected in 4\/4 (100%) pancreatic versus 0\/7 (0%) non-pancreatic tumors, respectively. These results suggest a potential role for gene fusions in triggering the ACTH production in pancreatic NENs presenting with ectopic Cushing syndrome. While the exact mechanisms responsible for the ectopic ACTH secretion are beyond the scope of this study, overexpressed fusion proteins might be involved in promoter-mediated overexpression of pre-ACTH precursors in analogy to the mechanisms postulated for <jats:italic>EWSR1::CREB1<\/jats:italic>-mediated paraneoplastic phenomena in certain mesenchymal neoplasms. The genetic background of the ACTH-producing non-pancreatic NENs remains to be further studied.<\/jats:p>","DOI":"10.1007\/s00428-022-03484-4","type":"journal-article","created":{"date-parts":[[2023,1,24]],"date-time":"2023-01-24T05:04:46Z","timestamp":1674536686000},"page":"507-516","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Gene fusions are frequent in ACTH-secreting neuroendocrine neoplasms of the pancreas, but not in their non-pancreatic counterparts"],"prefix":"10.1007","volume":"482","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0445-8161","authenticated-orcid":false,"given":"Abbas","family":"Agaimy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsuko","family":"Kasajima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Stoehr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Haller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Schubart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"T\u00f6gel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Pfarr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"von Werder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianne E.","family":"Pavel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fausto","family":"Sessa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Uccella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"La Rosa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00fcnter","family":"Kl\u00f6ppel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,1,24]]},"reference":[{"key":"3484_CR1","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1210\/jc.2005-1542","volume":"91","author":"AM Isidori","year":"2006","unstructured":"Isidori AM, Kaltsas GA, Pozza C, Frajese V, Newell-Price J, Reznek RH, Jenkins PJ, Monson JP, Grossman AB, Besser GM (2006) The ectopic adrenocorticotropin syndrome: clinical features, diagnosis, management, and long-term follow-up. 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